The present invention relates to a treatment for slowing or preventing the progression of osteoporosis in surgically or chemically castrated prostatic cancer patients.
Osteoporosis is generally the occurrence of a reduction in the quantity of bone, or the atrophy of skeletal tissue. This disorder is evidenced by a decrease in bone density throughout the body. Although the mechanism of osteoporosis is not entirely understood, it is believed that there is an imbalance between bone production and bone resorption, resulting in net bone resorption or breakdown. The condition can begin to occur as early as age 30. The process is typically more rapid in postmenopausal women than in men. Bone loss in males can be recognized at about 65 years of age. A significant bone loss is seen in men at about 80 years of age, and is accompanied by increased hip, spine and wrist fractures.
Surgical and chemical (e.g., LH-RH agonists) castration are widely used for the treatment of patients with prostate cancer. A number of side effects occur as a result of such therapy. Impotence and the occurrence of hot flashes are among the more distressing side effects to patients.
A less noted side effect of surgical or chemical castration is osteoporosis. It has been reported that orchiectomy for prostate cancer is often followed by severe osteoporosis (Daniell, H. W., J. Urol. 157:439-444, 1997). Castration of man and many animal species retards skeletal growth and development. Orchiectomy in rats can cause osteoporosis detectable from within two to four months. (Winks and Felts, Calcif. Tissue Res. 32:77-82 (1980); Verhas et al., Calcif. Tissue Res. 39:74-77 (1986)).
Unlike the evident side effects of orchiectomy or LH-RH agonist treatment, the pronounced onset of osteoporosis can be insidious since the risk of osteoporetic fracture increases rapidly. Moreover, these patients are preoccupied with adjusting to their treatment and addressing basic quality of life issues rather than taking measures to deter bone loss. Because of pain or their overall condition, many of these patients are not up to exercising, for instance.
It is thought that the sudden reduction in androgen levels effected by surgical castration or medical castration (e.g., LH-RH agonist treatment) in these men causes or is an important factor contributing to the degree of bone loss that can occur. (Daniell, H. W. J. Urol. 157:439-444, 1997). The correlation between the reduction in levels of adrenal estrogen in women during the menopause and the onset of osteoporosis is well known. In both sexes, the clinical situation can be described as an acquired gonadal insufficiency. Furthermore, it has been suggested that androgens increase the synthesis of bone matrix. Studies in animals have shown that testosterone administration increases the overall quantity of bone. (Silberberg and Silberberg, 1971; see Finkelstein et al., Ann. Int. Med. 106:354-361, 1987).
Estrogen replacement therapy has been the therapy of choice for osteoporosis in post-menopausal women. For men, estrogens may be effective to treat osteoporosis, but at the risk of gynecomastia and increased cardiovascular morbidity.
U.S. Pat. No. 5,541,172 to Labrie et al. addresses methods of treatment of diseases responsive to activation of the androgen receptor. The patent indicates methods for prevention and therapy of breast and endometical cancer, as well as osteoporosis. An androgenic steroid is administered such that circulating serum levels are maintained at low concentrations of between 1.0 and 50.0 nanomoles per liter. This cumulative dose is provided by administering the steroid within a sustained release formulation to avoid fluctuating blood levels.
Also discussed by the Labrie et al. patent are contentions that some synthetic progestins possess, in addition to their progesterone-like activity, varying degrees of androgenic activity. Labrie et al. indicate that progestins frequently have a high affinity for the androgen receptor at the low plasma concentrations mentioned. The patent reports on the use of medroxyprogesterone acetate and megestrol acetate. It also indicates that certain synthetic progestins or anabolic steroids including, for example, nor-testosterone, ethisterone and cyproterone acetate, possess androgenic activity at low concentrations in the in vitro system of human breast cancer ZR-75-1 cells.
The Labrie et al. patent advises assessing the specific interactions of a compound at the indicated concentrations with the androgen receptors, including estrogen, progesterone and glucocorticoid-mediated activities. At low concentrations, the compounds of interest to Labrie et al. do not interact with the glucocortioid receptor. Thus, masculinizing side effects of androgens in the treatment of women can be avoided. The patent further advises evaluating by in vitro assay the effects of a potential compound on the various receptors indicated in ZR-75-1 human breast cancer cells. The focus of the patent on the treatment of women who have diseases responsive to activation of the androgen receptor, particularly estrogen-dependent diseases, is apparent.
U.S. Pat. No. 5,567,695 to Labrie is related to the above discussed Labrie et al. patent and similarly reports a method for preventing osteoporosis. An androgenic steroid having a Ki of less than 2xc3x9710xe2x88x928M for the androgen receptor and having a receptor-mediated inhibitory effect on the growth of human breast cancer ZR-75-1 cells is used, where the dosage is sufficiently low to maintain a cumulative androgenic steroid serum concentration below 50 nanomoles per liter. Similar to the above Labrie et al. patent, the compounds are indicated to have the special property of potent androgenic activity at these low blood concentrations, while exhibiting little glucocorticoid activity, and therefore, they produce no visible masculinizing effects.
It has been suggested that progestational agents can potentiate bone mineralization, although the definitive effect of progesterone on bone is apparently not known. (Loprinzi, et al., N. Engl. J. Med. (1994) 331:347-352).
Cyproterone acetate (xe2x80x9cCPAxe2x80x9d) is disclosed in U.S. Pat. No. 3,234,093, which is incorporated herein by reference. CPA, a synthetic 21-carbon hydroxyprogesterone derivative, is a steroidal antiandrogenic agent that inhibits the action of adrenal and testicular androgens on prostatic cells, resulting in total androgen blockade. Additionally, due to the antigonadotropic effects of its progestogenic activity, CPA causes a centrally mediated reduction in testicular secretion of androgens. The progestational activity of CPA is considered relatively weak. (Goldenberg, S. L. et al., Pharmanual 1994, Current Perspectives on the Expanding Role of Androcur,(copyright) Pharma Libri Publishers Inc., at p. 21).
CPA is approved for use in many countries throughout Europe, Asia, Australia, South America and Canada. It is used as a component of oral contraceptives and in the treatment of acne, seborrhea, hirsutism, precocious puberty, hypersexuality and in the treatment of prostate cancer. The pharmaceutical preparations Androcur(copyright), Cyprostat(copyright), Diane(copyright) and Dianette(copyright) are CPA-based products. Manufacturers of these products include Schering AG, Berlin, Germany and Berlex, Canada.
Since 1966, CPA has been used in combination with bilateral orchiectomy to achieve total androgen blockade in the treatment of prostate cancer. CPA has also been administered as monotherapy for prostate cancer. The potent antiandrogenic activity of CPA is xe2x80x9ccancerocidalxe2x80x9d to prostate cancer cells. Dosages of 250-300 mg/day are used to bring about a complete anti-androgenic blockade. Dosages prescribed are usually 200-300 mg/day, divided into 2-3 doses. After orchiectomy a lower daily dose of 100-200 mg may be recommended. In a study reported in 1972 by Bracci and DiSilvero (discussed in Goldenberg, S. L. et al., Pharmanual 1994, Current Perspectives on the Expanding Role of Androcur,(copyright) Pharma Libri Publishers Inc., p. 23-24), CPA was administered at 100 mg/day or more with orchiectomy to patients with various advanced tumors for more than 2 years. The investigators noted that CPA in combination with orchiectomy has marked therapeutic effectiveness.
Side effects most frequently recorded with CPA treatment relate to the hormonal effects of the drug. These include impotence, inhibition of spermatogenesis and gynecomastia. These reactions are usually reversible upon discontinuation of therapy or reduction in dose. The drug is also associated with rapid falls in serum testosterone levels, which may also produce such central nervous system effects as fatigue, weakness, and headache.
CPA has a low incidence of side effects and its antigonadotropic and antiandrogenic effects are reversible, which enables intermittent therapy. Unlike other androgen deprivation therapies, CPA is rarely associated with hot flashes. Prostate cancer patients receiving CPA combined with surgical or chemical castration are less likely to experience hot flashes than those who do not receive CPA. (Barradell et al., Drugs and Aging (1994) 5/1:59-80.)
The Androcur(copyright) Monograph, Berlex Inc., Canada (1997), indicates a general improvement in the subjective assessment of the quality of life in 70% of 367 evaluable patients participating in worldwide studies on CPA, based on criteria of general improvement in quality of life. The criteria listed are weight gain and pain relief. In a large scale randomized clinical trial on patients who had previously undergone orchiectomy and who had the mere occurrence of hot flashes and/or outbreaks of sweat, the number of patients experiencing hot flashes or outbreaks of sweating decreased after 6 months of treatment with 150 mg/day CPA (50 mg. t.i.d.). (Kramer, P., et al., In: Murphy G., et al., 3rd Int""l Symposium on Recent Advances in Urological Cancer Diagnosis and Treatmentxe2x80x94Proceedings. Paris, France: SCI: 3-7 (1992)).
Another beneficial effect seen with CPA treatment has been the prevention of exacerbated bone pain. Patients with Stage C and D prostate cancer indicated improvement in bone pain with CPA as monotherapy. (Barradell et al., Drugs and Aging (1994) 5/1: 59-80). Overall, pain relief has been noted in 50-80% of patients receiving treatment with ANDROCUR(copyright). (The Androcur Monograph, Berlex, Canada (1997)). The effect of CPA on pain generally paralleled its effect on metastasis. Id. When metastasis remained improved or stabilized, the analgesic requirement was also reduced. Id.
It has also been reported that exacerbated bone pain associated with the flare reaction at the start of LH-RH agonist treatment is prevented with CPA administered to prevent acute flare-up of prostatic disease. The Goldenberg, S. L. et al., Pharmanual (cited above), indicates that Claes H., et al., in Murphy G P (Prostate Cancer, Part A: Research, Endocrine Treatment, and Histopathology, New York, N.Y.: Alan R. Liss (1987) 229-236), found that 58.5% of 17 patients who received goserelin alone experienced a transient increase in bone pain compared with none of 7 patients who received goserelin acetate plus 200 mg/day CPA. For the short-term prevention of tumor flare, CPA has been administered with an LH-RH agonist generally at 150 to 300 mg/day dosages. Also for tumor flare, CPA has been administered at 100 mg/day in combination with 0.1 mg/day of the estrogen diethylstilbestrol (DES). (Bruchovsky et al., Cancer 71: 7282-2790 (1993)).
Dose-related hepatic toxicity in humans has been reported with the prolonged use of CPA. Toxicological studies have revealed, however, that administration of CPA to humans does not pose a serious risk of hepatotoxicity. A retrospective liver toxicity analysis was performed on 89 patients with advanced prostatic cancer who underwent orchiectomy and who received continuous additional antiandrogenic treatment with 50 mg/day CPA. (Hinkel et al., Eur. Urol. (1996) 30:464-470). CPA was administered to these patients for a period spanning from 2 to 152 months starting at the time of diagnosis. Various medications were frequently prescribed besides CPA treatment. Although a proper control group was lacking, in no case was CPA discontinued due to its side effects. After evaluating the patients"" liver function, the authors concluded that CPA is a reliable drug to inhibit androgen synthesis with maximum efficacy and safety in the treatment of prostate cancer.
A review on the toxicology of CPA was published by Rabe et al. (Drug Safety (1996 (January)); 14(1):25-38). In a multi-center surveillance study of long term CPA use in over 2500 patients, the treatment group included men and women. The men were treated at dosages of either more than 200 mg/day or from 100 to 200 mg/day CPA. No correlation was found between the duration of CPA treatment and the prevalence of liver enzyme elevations. Not a single case of hepatocellular carcinoma was observed. The authors concluded that there were no observations that would indicate an increased risk of proliferative liver change as a result of CPA treatment.
The Androcur(copyright) Monograph, Berlex, Canada (1997) reports on the pharmacokinetics of CPA in humans. It indicates that the mean plasma concentration of CPA in male subjects following oral administration of one 50 mg dose is about 700 nmol/L. Continual dosing of 50 mg per day CPA would be expected to result in a plasma level of CPA maintained at an estimated concentration from about 500 to about 750 nmol/L, and upon a longer period of continual dosing, the cumulative plasma level would likely be closer to a steady state level of about 750 nmol/L or higher. Blood levels of CPA are known to be generally dose dependent.
The minimum dosage of CPA for an antigonadotropic effect in men may not be precisely known. The threshold value for an antiandrogen effect in men was indicated to be 50 mg according to U.S. Pat. No. 3,895,110, which issued in 1975. Presumably then, the threshold value for an anticancerocidal dosage in prostate cancer patients may also be 50 mg.
CPA is generally not considered an androgenic compound. In fact, CPA is therapeutically classified as an anti-androgen (Androcur(copyright) Monograph, Berlex, Canada, 1997), and is used clinically for its potent anti-androgenic activity in the treatment of prostate patients, as discussed. In a critical review of possible paradoxical androgenic activity of CPA (El Etreby et al., The Prostate 11:361-375 (1987)), the authors caution that the circumstances under which paradoxical androgen-like effects may develop are of significance. For example, inhibition of complete involution of the ventral prostate of castrated adult rats by CPA was shown to be very weak, and these results were not seen with higher doses of CPA. It was suggested that the effect may not be related to an asserted androgenicity, but rather, to an inhibitory effect on prostatic catabolic activities. The authors also explain that CPA does not meet the classical definition of an androgenic steroid xe2x80x9cbecause of its inability to restore the normal size and function of adult prostates even if administered to castrated animals with involuted prostates at doses high enough and for a sufficiently long time.xe2x80x9d (El Etreby et al.)
Estrogens have a testosterone-reducing effect that is based to a large extent on the increased release of inhibitory factors from the hypothalamus in addition to a direct effect on the pituitary gland.
Goldenberg et al. (J. Urol. (1988) 140: 1460-1465) reported that CPA and low dose DES may be co-administered to achieve a synergistic androgen withdrawal effect in the treatment of advanced prostatic carcinoma. CPA administered at 200 mg/day with 0.1 mg daily DES showed a marked decrease in serum testosterone, with no change upon decreasing CPA to 100 mg/day in the combination. In a subsequent report, Goldenberg et al. (Urology 47 (6) (1996) 882-884) indicate that 100 mg CPA and 0.1 mg DES per day result in a persistent decrease in serum testosterone with a lower incidence of side effects than the 200 mg/day CPA combination. Bruchovsky et al. (Cancer 71: 2782-2790 (1993)) report elimination of flare reaction by pretreatment with CPA and low-dose DES. Patients were pretreated with 100 mg per day CPA and 0.1 mg/day DES for 4 weeks. Goserelin acetate was then given and CPA/DES was continued. DES administration was discontinued at 8 weeks to eliminate associated minor toxicity.
Goldenberg et al. (J. Urol. (1988) 140: 1460-1465) indicate that a weakening of the antigonadotropic effect of CPA, seen after 6 to 9 months, was not observed with the continued co-administration of DES.
Chlorotrianisene, an estrogen which was sold in the United States under the name TACE(copyright), was indicated for the palliative therapy of advanced prostatic carcinoma and for moderate to severe vasomotor symptoms associated with the menopause, among other things. For long-term treatment of progressive prostatic cancer, 12 mg to 25 mg daily was prescribed. (Physicians"" Desk Reference, 35th Edition (1981)).
It has also been forwarded that estrogens may increase prostatic cancer growth. In the treatment of prostate cancer, U.S. Pat. No. 5,610,150 discloses a combination therapy for prostate cancer treatment that includes an antiandrogen, a sex steroid biosynthesis inhibitor and an antiestrogen for the prevention of the biosynthesis of estrogen.
It has been reported that serum osteocalcin (OC) can be useful clinically as a marker to monitor patients with bone metastases. After testing with various anticancer treatment strategies, low dose CPA included, Tarle, M. (Urol. Res. (1991) 19:39-44) reported that OC concentration can serve as a nonspecific marker of bone lesions in patients with prostatic carcinoma. As a bone-derived protein related to mineralization processes during bone healing, elevated OC can indicate remission in patients with advanced prostatic cancer.
There is no suitable treatment for osteoporosis in surgically or chemically castrated prostatic cancer patients. A method for treating osteoporosis that is compatible with androgen ablation therapy of prostate cancer will fulfill an important medical need.
The present invention provides a method for preventing or treating osteoporosis in a castrated prostatic cancer patient, by administering to the patient an amount of from 10 mg to 300 mg cyproterone acetate per day. The present therapy is compatible with the patients"" anti-cancer treatment.